Medicinal composition



Patented June 17, 1941 MEDICINAL COMPOSITION Charles William Schaiferand Reinhard Beutner, Philadelphia, Pa.

No Drawing. Application January 21, 1938, Serial No. 186,086

9 Claims.

The present invention relates to a medicinal composition intended forthe treatment of various diseased conditions by the provision of iodinein therapeutically active form.

Most of the therapeutically used iodine compounds have a transitory andinadequate thera-- peutic action. The inorganic iodides are rapidlyexcreted; and the same is true for most iodo proteins since the iodineis split off in the form of hydriodic acid or inorganic salts which areexcreted. In the iodized fats, on the other hand, iodine is so tightlybound that it is not available for the body.

The present invention is concerned with a hitherto unknown class of iodoproteins and similar iodine compounds, the iodine of which is readilyavailable in the body. The iodine made available by these compounds maybecome therapeutically active in two possible ways. In the firstalternative, the available iodine may be transferred to tyrosine to formdi-iodo-tyrosine, and related compounds which condense to form thyroxin,while in the second alternative preformed iodo-tyrosine and relatedproducts may be split off from an iodo protein and transformed intothyroxin.

Of these two alternatives mentioned above leading to the formation ofthyroxin, our experience leads us to favor the first possibility as thatactually occurring, since our improved composition comprises substancescontaining iodine, the iodine of which we have found readily passes froman aliphatic chain into an aromatic ring at a temperature as low as 350., preferably in the presence of oxidizing agents. Such an iodinationis quite extraordinary and unexpected, since even free iodine does notenter into combination with benzene atsuch a low temperature as 35 C. Wehave also investigated which other iodine-containing compounds have thepeculiar property of transferring iodine in such a manner, and havefound that beta-iodo-propionic acid, as well as other beta-iodo fattyacids, will readily transfer their iodine to benzene at a lowtemperature in the presence of oxidizing agents. We have also found thattyrosine may be iodized to di-iodotyrosine by treatment withbeta-iodo-propionic acid in the presence of oxidizing agents such ashydrogen peroxide at 35 0., whereas free iodine never iodizes tyrosineat such a low temperature. Alpha-iodo fatty acids, however, will nottrans fer their iodine to an aromatic nucleus under the samecircumstances. Hence it may, perhaps be concluded that our newiodo-proteins likewise contain iodine tied up to a beta-carbon atom, al-

though it is possible that the iodine may be attached to a delta-carbonatom.

As stated, the transfer of iodine from a beta carbon atom is facilitatedby the oxidation process occurring in the tissues. It has beendemonstrated that oxidation of proteins and organic acids in generalalways sets in at the beta carbon atom. Our experiments indicate that ifiodine is attached in a beta, or possibly delta, position to analiphatic compound it is set free by oxidation and becomes readilytransferred to an aromatic nucleus, as, for example, tyrosine.

While beta-iodo-propionic acid and other betaiodo fatty acids can beused as iodizing agents for therapeutic purposes since they readilytransfer their iodine leading to the formation of iodo tyrosine and thenthyroxin in the tissues of the body, we have found it preferable to formproteins which probably contain iodine on a beta carbon by the methoddescribed below and to use these proteins for therapeutic purposes sinceiodo proteins are much easier to ingest than the iodized lower fattyacids.

Included in this application within the scope of the term protein" arepeptides and peptones which function in both their chemical andtherapeutic behaviors in the same fashin as proteins.

Apparently the therapeutic value of the betaiodo proteins hereindescribed is primarily due to their beta-iodization, although not all oftheir iodine is bound in this fashion nor is the otherwise bound part ofthe iodine entirely inactive. A part of the iodine in these proteins ismerely adsorbed to the protein and becomes readily available foriodization in the body. This free adsorbed iodine can be determined byextraction with othersolvents. In the proteins iodinated according toour method, the adsorbed iodine represents only a fraction of the totaliodine present, whereas in proteins icdinated by Lugols solution nearlyall the iodine may be extracted with alcohol.

For the preparation of iodo proteins having the desirable propertiesindicated herein we preferably react a sodium proteinate with or withoutan excess of alkali, or a solution of such a proteinate, with an organicor other weak acid in which free iodine has been dissolved. The quantityof iodine used should amount to 5%-50% of the weight of the protein.Preferably the quantity of the acid employed should substantiallyexactly neutralize the alkali combined with or added to the protein,though neutralization is no indispensable requisite of our process. Theacids used may be, for example, lactic, acetic, propionic,

phosphoric or butyric used alone or in admixture with alcohols or otheriodine solvents, or in aqueous solution. If the alkali bound to theprotein is not entirely neutralized by the addition of an acid, some ofthe added iodine will interact with it to form alkali iodate.

The proteins which are preferably used in this process include serumprotein, vegetable protein, albumins of various origins, casein, orother proteins in the form of their sodium salts. The iodizing reactionis carried on at 25 to 45 C. with agitation to facilitate the reactionsat definite dilution, depending on the solubility of the sodiumproteinates used. As an example of a specific preparation there may becited the treatment of sodium caseinate, or another sodium proteinate,to form the corresponding beta-iodo protein. The sodium proteinate isdissolved in water to form a solution or emulsion containing from 5% to30% thereof. This is warmed to 35 to 45 C. and mixed with lactic acid oranother acid in which 20% to 30% by weight of iodine is dissolved. Underthese circumstances neutralization is effected and the protein isprecipitated. After and during precipitation and coagulation the proteinis gradually iodized by the iodine present. It is theniiltered, washedand dried, preferably in vacuo, at a temperature desirably not exceeding60 C. The temperature is so limited so as not to completely dehydratethe iodo protein, which might thus be rendered undigestable in the body.It may be here noted that the yield in the case of sodium caseinate isabout 90%. Proteins of the conjugated type are generally broken downinto simpler protein constituents in the process. In conjugated proteinssuch as casein the amino groups are protected by a type of peptidestructure already existing therein. In the case of some proteins, forexample, albumins, it may be necessary to preliminarily peptize theprotein in order to protect the amino groups against substitution ofiodine for their hydrogen atoms. 7

If proteins iodinated by this method are treated with hydrogen peroxidein an acidic medium, they readily liberate iodine; and in contact withtyrosine they form di-iodo tyrosine. These reactions prove that theiodine in these proteins is readily transferable, in a fashion similarto the exchange of iodine in iodo-propionic acid and in the body. Henceit is very probable that the iodine in the proteins is also attached ina beta position, though because of the complexity of the protein it israther diflicult to be certain that this is the case. We have discoveredthat the transfer of iodine to tyrosine to form di-iodo-tyrosine in thepresence of hydrogen peroxide in an acid medium at low temperatures ofthe order of 35 C. may be used as a test of the emcacy of the iodoproteins for their intended therapeutic use. Consequently, where weherein refer to beta-iodo proteins (which our compounds appear to be),we wish to be understood as meaning such iodo proteins as will transfertheir io he to tyrosine when treated with hydrogen per de in an acidmedium or in the presence of acidic ions at 35 C.

In addition to the iodine which is chemically bound, our iodo proteinscontain free adsorbed iodine which may be extracted by alcohol or othersolvents for iodine, though it is not extracted by dilute hydrochloricacid or by the gastric juice. This adsorbed iodine appears to be ofimportance, since our experiments indicate that it acts catalytically inconjunction with the iodine apparently bound in the beta position.

Of the compounds heretofore investigated, beta-iodo-casein has beenfound most satisfactory, although it appears that substantially anyprotein may be used in the iodinated form of the type described.

As contrasted with our iodo proteins, the iodized proteins heretoforeproduced will not iodinate tyrosine under the action of hydrogenperoxide at 35 0. Our iodo proteins are also differentiated from thoseheretofore produced by the extractibility of a much lower percentage ofthe total iodine content by alcohol or water, the former removingadsorbed iodine which has been the primary type of iodine present inprevious compounds, and the latter removing salts of iodine.

While the complicated structures of protein type are preferably used toform the basis for the therapeutic beta-iodo compounds, it is possibleto utilize simpler compounds, though their use is not so desirable. Forexample, alpha-amino-propionic acid may be treated with iodine in afashion similar to that indicated above to formbetaiodo-alpha-amino-propionic acid, which may be used in a fashionsimilar to the beta-iodo proteins. which, it may be noted, are ingeneral beta-iodoalpha-amino acids combined in the protein molecule. Inthe case of iodization of saturated a1- pha-amino acids hydriodic acidis formed, which should be taken care of by the provision of the properamount of alkali.

In general it may be said that the improved medicinal compositionscomprise the class of beta-iodo compounds in which there is attached tothe alpha carbon atom a carboxyl, hydroxyl, amino, or sulphonic acidgroup. These compounds may contain various substituents, primarily aminogroups in the alpha position, as well as aliphatic or aromatic groups.The compounds containing alpha amino groups are exemplified by thebeta-iodo proteins and by the beta-iodo-alpha-amino-propionic acidmentioned above.

The useful compounds may be structurally indicated as comprising thegrouping R2CI.CR2'.R" in which R" is a COOH, OH or SOeH group, both oreither R may be almost any group of non-toxic character, and both oreither R may be almost any group of non-toxic character provided it doesnot inhibit liberation of the I by physiological oxidat ion, as is thecase if either R is 9. 0001-! or SOsI-I group.

More specifically, the more desirable compounds are carboxylic acids (ortheir derivative) which may be structurally indicated by RACI.CR2'.COOH

in which R and B may be as indicated above.

The most desirable compounds contain the structure RBCI-CR/(NH2) .0001!in which R and R may be as indicated above. The proteins, peptides andpeptones are complicated examples of this group of compounds. Allrvlsubstituents may replace the hydrogen of the amino group or groups.

It will be understood that where references are made to these compoundsin the appended claims, their salts, homologues and derivatives areincluded. It will also be understood that by reference to iodo proteinsit is intended to include iodo peptides and iodo peptones which areclosely :flated thereto and may be regarded as derivaves. The iodinatediodinated) prepared in accordance with the above processes have beenextensively applied in clinical compounds (apparently betaresearch,particularly in the conditions in which iodides are customarily given,for example, arthritis, rheumatism, syphilis, hypertension, thy- -roiddisfunction and obesity. The new compounds have invariably been found tohave a low toxicity and a much greater effectiveness in the above namedconditions than the hitherto used iodo proteinate compounds. Theimproved compounds may be administered orally. In the case of theproteins they may be administered as such or in the form of salts. Eveninsoluble conjugated proteins are dissolved in the digestive tract intosimpler fractions available for therapeutic action.

What we claim and desire to protect by Letters Patent is:

1. A composition for the treatment of pathological conditions comprisingan iodo carboxylic acid capable of transferring its iodine to anarcmatic compound in the presence of hydrogen peroxide at 35 C.

2. A composition for the treatment of pathological conditions comprisingan iodo-alphaamino carboxylic acid capable of transferring its iodine toan aromatic compound in the presence of hydrogen peroxide at 35 C.

3. A composition for the treatment of pathological conditions comprisingan iodo-protein capable of transferring its iodine to an aromaticcompound in the presence of hydrogen peroxide at C.

4. A composition for the treatment of pathological conditions comprisingan iodo conjugated protein capable of transferring its iodine to anaromatic compound in the presence of hydrogen peroxide at 35 C.

5. A composition for the treatment of pathological conditions comprisingan iodo casein capable of transferring its iodine to an aromaticcompound in the presence of hydrogen peroxide at 35 C.

6. The method of forming an iodo protein comprising reacting iodine insolution in an organic acid with an alkali proteinate.

'7. The method of forming an iodo protein comprising reacting iodine inacid solution with an alkali proteinate.

8. The method of forming an iodo protein comprising reacting iodine inacid solution with an alkali caseinate.

9. The method of forming an iodo protein comprising reacting iodine inan acid and an iodine solvent with an alkali proteinate.

